This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although noroviruses (NIAID category B priority pathogen) are a major public health concern with their ability to cause large outbreaks of acute gastroenteritis, the lack of a cell culture system greatly hinders research on preventive measures, such as the developments of vaccines and antiviral drugs. The long term goal of this application is to understand the replication of noroviruses. Novel cell based norovirus replication system (Norwalk virus [NV] replicon-bearing cells), which we developed recently, will be used for studying replication and antivirals of noroviruses. Especially we will focus on the effects of IFNs on the replication of NV. We plan to generate additional norovirus replicon-bearing cells using different norovirus strains adapting the similar strategy for that of NV replicon bearing cells in searching for strains efficiently replicate in cells. Because we found the bile acids and cholesterol pathways were important in growing the related virus, porcine enteric calicivirus (PEC) in cell culture, we will examine bile acids/cholesterol pathways in the replication of norovirus. Specifically, we will examine farnesoid X receptor (FXR) and G protein couple receptor (TGR5) of bile acids in the replication of norovirus. These studies should contribute to the isolation of noroviruses in cell culture, which is a key for development of preventive strategies to control diarrheal disease caused by noroviruses.